The core aim of this project is to elucidate the nature, molecular foundations, underlying neurochemistry, and clinical correlates of neural systems-level dysfunction in schizophrenia. Toward that end, this year, the Section on Integrative Neuroimaging has successfully executed comprehensive, multimodal positron emission and magnetic resonance based studies of a unique and steadily growing cohort of individuals with schizophrenia who have agreed to be studied under placebo (medication-free) conditions as well as matched healthy individuals. Though this work is necessarily challenging to conduct, we have made substantial progress in data collection, which now includes characterization of dopamine-dependent mnemonic and reward-related neural responses, striatal presynaptic dopamine synthetic capacity, and both D1 and D2/3 receptor availability. Modern antipsychotic treatments have heterogeneous effects across individuals and often leave many symptoms (e.g., cognitive) untreated, though the biological mechanisms underlying these clinical problems remain largely mysterious. Our most recent work has been particularly focused on advancing evolving knowledge of antipsychotic medication response, yielding novel insights into the neurochemical predictors of neuroleptic-driven changes in brain activity and symptom burden. Specifically, we have taken advantage of the ability to study people with schizophrenia in the medicated and medication-free state and sought to quantify the impact of antipsychotic treatment on striatal regional cerebral blood flow, as measured by PET. In preliminary studies, medication induces robust increases in striatal blood flow. We are now completing follow-up investigations evaluating the degree to which this increase predicts the amount of medication-related therapeutic improvement, suggesting that this response may be an important biomarker. We are also employing concurrent 18FDOPA PET studies to test the hypothesis that variability in this physiological response might be due in part to trait differences in dopaminergic tone. We have additionally found that antipsychotic medications increase the amount of GABA in the anterior cingulate cortex. Although GABA levels do not appear to be predictive of symptom change, preliminary data suggest that glutamate levels in the same region might be moderately negatively associated with antipsychotic response, indicating that patients with high glutamate might derive lesser benefit from currently available drugs with a dopaminergic mechanism. The observation that complex, multi-receptor systems are at play in the mechanisms underlying medication response are echoed by collaborative work identifying interactions between genes for the dopamine D2 and serotonin 5-HT2A receptors that affect clinical response to antipsychotic treatment. Finally, we are completing two personalized-medicine drug trials examining interactions between genotype for COMT, an enzyme important for maintaining cortical dopamine, and effects of dopamine-modulating medication on cognitive function in schizophrenia. In sum, these integrative, multimodal clinical data bridge an important gap between pharmacotherapeutics, neurophysiology and neurochemistry, creating a foundation for progress in better understanding key elements of antipsychotic action and failure. This work involves the following studies: NCT00942981, NCT00001258, NCT00024622, NCT00004571, NCT00001247, NCT00044083, NCT00057707